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Colorectal carcinomas containing hypermethylated MLH1 promoter and wild type BRAF/KRAS are enriched for targetable kinase fusions

Emiliano Cocco, Jamal Benhamida, Sumit Middha, Ahmet Zehir, Kerry Mullaney, Jinru Shia, Rona Yaeger, Liying Zhang, Donna Wong, Liliana Villafania, Khedoudja Nafa, Maurizio Scaltriti, Alexander Drilon, Leonard Saltz, Alison M. Schram, Zsofia K. Stadler, David M. Hyman, Ryma Benayed, Marc Ladanyi and Jaclyn F Hechtman
Emiliano Cocco
Department of Obstetrics, Gynecology and Reproductive Sciences, Memorial Sloan Kettering Cancer Center
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Jamal Benhamida
Department of Pathology, Memorial Sloan Kettering Cancer Center
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Sumit Middha
Department of Pathology, Memorial Sloan Kettering Cancer Center
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Ahmet Zehir
Department of Pathology, Memorial Sloan Kettering Cancer Center
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Kerry Mullaney
Department of Pathology, Memorial Sloan Kettering Cancer Center
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Jinru Shia
Department of Pathology, Memorial Sloan Kettering Cancer Center
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Rona Yaeger
Department of Medicine, Memorial Sloan Kettering Cancer Center
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Liying Zhang
Department of Pathology, Memorial Sloan Kettering Cancer Center
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Donna Wong
Department of Pathology, Memorial Sloan Kettering Cancer Center
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Liliana Villafania
NGS Diagnostic Molecular Oncology, Memorial Sloan Kettering Cancer Center
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Khedoudja Nafa
Department of Pathology, Memorial Sloan Kettering Cancer Center
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Maurizio Scaltriti
Department of Pathology, Memorial Sloan Kettering Cancer Center
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Alexander Drilon
Department of Medicine, Memorial Sloan Kettering Cancer Center
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Leonard Saltz
Medicine, Memorial Sloan Kettering Cancer Center
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Alison M. Schram
Department of Medicine, Memorial Sloan Kettering Cancer Center
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Zsofia K. Stadler
Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College
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David M. Hyman
Department of Medicine, Memorial Sloan Kettering Cancer Center
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Ryma Benayed
Memorial Sloan Kettering Cancer Center
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Marc Ladanyi
Memorial Sloan Kettering Cancer Center
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Jaclyn F Hechtman
Department of Pathology, Memorial Sloan Kettering Cancer Center
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  • For correspondence: hechtmaj@mskcc.org
DOI: 10.1158/0008-5472.CAN-18-3126
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Abstract

Kinase fusions are rare and poorly characterized in colorectal carcinoma (CRC), yet they present unique opportunities for targeted therapy. In this study, we characterized kinase fusions from patients with advanced CRC who had MSK-IMPACT testing of their tumors between January 2014 and June 2018. Patients were analyzed for the presence of fusions, microsatellite instability (MSI), and RAS/BRAF mutations. Mismatch repair (MMR) immunohistochemistry (IHC) and promoter hypermethylation status of MLH1 (MLH1ph) in MSI-H CRC with fusions were investigated. Fusion transcripts were confirmed using a targeted RNAseq panel assay. Of 2314 CRCs with MSK-IMPACT testing, 21 harbored kinase fusions. Overall 57% (12/21) of CRC fusions were MSI-H/MMR-D. Loss of MLH1 and MLH1ph was confirmed in all 12 and all 10 cases with available material, respectively. Fusions were present in 5% of MSI-H/MMR-D CRC compared to 0.4% of MSS/MMR-P CRC (p<0.001), and 15% of MSI-H/MMR-D CRC with wild type RAS/BRAF. Of 24 total MLH1-deficient CRC with MLH1ph and wild type RAS/BRAF, 10 (42%) harbored kinase fusions. Kinase fusions in MSI-H CRC were associated with sporadic MLH1ph rather than with Lynch syndrome, and these patients may be eligible for kinase inhibitors, particularly following resistance or toxicity in response to immunotherapy. These findings identify a molecular subset of CRC with kinase fusions that may be responsive to kinase inhibitors.

  • Received October 3, 2018.
  • Revision received November 16, 2018.
  • Accepted January 8, 2019.
  • Copyright ©2019, American Association for Cancer Research.

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Published OnlineFirst January 14, 2019
doi: 10.1158/0008-5472.CAN-18-3126

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Colorectal carcinomas containing hypermethylated MLH1 promoter and wild type BRAF/KRAS are enriched for targetable kinase fusions
Emiliano Cocco, Jamal Benhamida, Sumit Middha, Ahmet Zehir, Kerry Mullaney, Jinru Shia, Rona Yaeger, Liying Zhang, Donna Wong, Liliana Villafania, Khedoudja Nafa, Maurizio Scaltriti, Alexander Drilon, Leonard Saltz, Alison M. Schram, Zsofia K. Stadler, David M. Hyman, Ryma Benayed, Marc Ladanyi and Jaclyn F Hechtman
Cancer Res January 14 2019 DOI: 10.1158/0008-5472.CAN-18-3126

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Colorectal carcinomas containing hypermethylated MLH1 promoter and wild type BRAF/KRAS are enriched for targetable kinase fusions
Emiliano Cocco, Jamal Benhamida, Sumit Middha, Ahmet Zehir, Kerry Mullaney, Jinru Shia, Rona Yaeger, Liying Zhang, Donna Wong, Liliana Villafania, Khedoudja Nafa, Maurizio Scaltriti, Alexander Drilon, Leonard Saltz, Alison M. Schram, Zsofia K. Stadler, David M. Hyman, Ryma Benayed, Marc Ladanyi and Jaclyn F Hechtman
Cancer Res January 14 2019 DOI: 10.1158/0008-5472.CAN-18-3126
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Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
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